EP3426664B1 - Substituierte nukleosid-analoga zur verwendung als prmt5-inhibitoren - Google Patents

Substituierte nukleosid-analoga zur verwendung als prmt5-inhibitoren Download PDF

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EP3426664B1
EP3426664B1 EP17706513.3A EP17706513A EP3426664B1 EP 3426664 B1 EP3426664 B1 EP 3426664B1 EP 17706513 A EP17706513 A EP 17706513A EP 3426664 B1 EP3426664 B1 EP 3426664B1
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alkyl
group
hydrogen
independently
halo
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French (fr)
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EP3426664A1 (de
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Didier Jean-Claude Berthelot
Dirk Brehmer
Lijs Beke
An Boeckx
Gaston Stanislas Marcella Diels
Ronaldus Arnodus Hendrika Joseph Gilissen
Edward Charles LAWSON
Vineet PANDE
Marcus Cornelis Bernardus Catharina PARADÉ
Wim Bert Griet Schepens
Brian Christopher Shook
Johannes Wilhelmus John F. Thuring
Marcel Viellevoye
Weimei SUN
Tongfei Wu
Lieven Meerpoel
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Janssen Pharmaceutica NV
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Janssen Pharmaceutica NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/167—Purine radicals with ribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/23—Heterocyclic radicals containing two or more heterocyclic rings condensed among themselves or condensed with a common carbocyclic ring system, not provided for in groups C07H19/14 - C07H19/22

Definitions

  • the present invention relates to novel substituted nucleoside analogues useful as PRMT5 inhibitors.
  • the invention further relates to pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.
  • PRMT5 also described as Hsl7, Jbp1, Skb1, Capsuleen or Dart5
  • Hsl7, Jbp1, Skb1, Capsuleen or Dart5 is one of the major methyltransferases responsible for mono- and symmetric dimethylation of arginines.
  • Post-translational arginine methylation on histones and non-histone proteins seems to be crucial for a variety of biological processes, like genome organisation, transcription, differentiation, spliceosome function, signal transduction and regulation of cell-cycle progression, stem cells and T-cell fate [ Stopa, N. et al., Cell Mol Life Sci, 2015. 72(11): p. 2041-59 ] [ Geoghegan, V. et al., Nat Commun, 2015. 6: p. 6758 ].
  • Metazoan PRMT5 forms a functional complex with the methylosome protein 50 (MEP50) also named as Wdr77, androgen receptor coactivator p44 and Valois. Both, elevated PRMT5-MEP50 protein level and cytoplasmic accumulation are implicated in cancer tumorigenesis and have recently been correlated with poor clinical outcome [ Shilo, K. et al., Diagn Pathol, 2013. 8: p. 201 ]. Cellular rescue experiments that addressed both the catalytic and scaffold function of the PRMT5-MEP50 complex, beside comprehensive enzymological studies have substantiate the oncogenic link between protein level, localisation and enzymatic function [ Gu, Z. et al., Biochem J, 2012. 446(2): p.
  • PRMT5 is a member of the type II PRMT subfamily that utilises S-adenosylmethionine (SAM) to generate symmetric dimethylated arginine on histones and non-histone protein substrates and S-adenosylhomocysteine (SAH).
  • SAM S-adenosylmethionine
  • SAH S-adenosylhomocysteine
  • PRMT5 human hetereo-octameric complex
  • MEP50 histone H4 peptide substrate illustrated the mechanism of methylation and substrate recognition [ Antonysamy, S. et al., Proc Natl Acad Sci U S A, 2012. 109(44): p. 17960-5 ].
  • the regulation of PRMT5 activity occurs through a vast number of different binding partners, post-translational modification cross talk, miRNAs and subcellular localisation.
  • Non-histone methylation can occur either in the cytoplasm or nucleus dependent on the cellular localisation of PRMT5.
  • Further evidence for PRMT5 involved in splicing has been provided by the conditional PRMT5 knockout in mouse neural stem cells. Cells that lack PRMT5 showed a selective retention of introns and skipping of exons with weak 5' donor sites [ Bezzi, M. et al., Genes Dev, 2013. 27(17): p. 1903-16 ].
  • PRMT5 influences key pathways involved in cell fate and homeostasis by direct methylation of key signalling nodules like p53 [ Jansson, M. et al., Nat Cell Biol, 2008. 10(12): p. 1431-9 ], EGFR [ Hsu, J.M. et al., Nat Cell Biol, 2011. 13(2): p. 174-81 ], CRAF [ Andreu-Perez, P. et al., Sci Signal, 2011. 4(190): p. ra58 ], PI3K/AKT [ Wei, T.Y. et al., Cell Signal, 2014. 26(12): p. 2940-50 ], NF ⁇ B [ Wei, H. et al., Proc Natl Acad Sci U S A, 2013. 110(33): p. 13516-21 ].
  • PRMT5 is one of the major sym-Arg methyltransferases and involved in a multitude of cellular processes, an increased protein expression appears to be an important factor in its tumourigenicity.
  • MCL mantle cell lymphoma
  • miRNAs the translation of PRMT5 in mantle cell lymphoma (MCL) seems to be regulated by miRNAs.
  • MCL cells show less mRNA and a slower transcription rate of PRMT5 than normal B lymphocytes, the PRMT5 level and the methylation of H3R8 and H4R3 are significantly increased [ Pal, S. et al., EMBO J, 2007. 26(15): p. 3558-69 ].
  • PRMT5 is considered as a clinical relevant target, very few selective PRMT5 inhibitors have been published, yet. Very recently, a novel sub-nanomolar potent PRMT5 inhibitor (EPZ015666) with anti-tumour activity in multiple MCL xenograft models has been described to be the first chemical probe suitable for further validation of PRMT5's biology and role in cancer [ Chan-Penebre, E. et al., Nat Chem Biol, 2015. 11(6): p. 432-7 ].
  • WO2014100695A1 discloses compounds useful for inhibiting PRMT5 activity; Methods of using the compounds for treating PRMT5-mediated disorders are also described.
  • WO2014100730A1 discloses PRMT5 inhibitors containing a dihydro- or tetrahydroisoquinoline and uses thereof.
  • WO2003070739 discloses partial and full agonists of Al adenosine receptors, their preparation, and their therapeutic use.
  • WO2012082436 discloses compounds and compositions as modulators of histone methyltransferases, and for treating diseases influenced by modulation of histone methyltransferase activity.
  • WO2012075500 discloses 7-deazapurine modulators of histone methyltransferase, and methods of use thereof.
  • WO2016l35582 and US20160244475 describe substituted nucleoside derivatives useful as anticancer agents.
  • WO2014100719 discloses PRMT5 inhibitors and uses thereof.
  • WO03074083 discloses combination therapies that selectively kill methylthioadenosine phosphorylase deficient cells. Analogs of MTA are described herein as anti-toxicity agents.
  • the compounds of the present invention are useful as PRMT5 inhibitors.
  • the compounds according to the invention and compositions thereof may be useful for the treatment or prevention, in particular for the treatment, of diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, and the like.
  • the present invention concerns novel compounds of Formula (I): wherein
  • the present invention also concerns methods for the preparation of compounds of the present invention and pharmaceutical compositions comprising them.
  • the compounds of the present invention were found to inhibit PRMT5 per se or can undergo metabolism to a (more) active form in vivo (prodrugs), and therefore may be useful in the treatment or prevention, in particular in the treatment, of diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, and the like.
  • diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries, and the like.
  • the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof may be suitable in the treatment or prevention, in particular in the treatment, of any one of the diseases or conditions mentioned hereinbefore or hereinafter, in particular cancer.
  • the present invention also concerns the use of compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the inhibition of PRMT5, for the treatment or prevention of any one of the diseases or conditions mentioned hereinbefore or hereinafter, in particular cancer.
  • the present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
  • substituted is used in the present invention, it is meant, unless otherwise is indicated or is clear from the context, to indicate that one or more hydrogens, in particular from 1 to 3 hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, on the atom or radical indicated in the expression using "substituted” are replaced with a selection from the indicated group, provided that the normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent.
  • substituents When two or more substituents are present on a moiety they may, unless otherwise is indicated or is clear from the context, replace hydrogens on the same atom or they may replace hydrogen atoms on different atoms in the moiety.
  • Het 2a and Het 2b may be attached to the remainder of the molecule of formula (I) through any available ring carbon or heteroatom as appropriate, if not otherwise specified.
  • the heterocyclyl when the heterocyclyl is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and the like.
  • C x-y (where x and y are integers) as used herein refers to the number of carbon atoms in a given group.
  • a C 1-4 alkyl group contains from 1 to 4 carbon atoms
  • a C 1-3 alkyl group contains from 1 to 3 carbon atoms and so on.
  • halo as a group or part of a group is generic for fluoro, chloro, bromo, iodo unless otherwise is indicated or is clear from the context.
  • C 1-4 alkyl refers to a hydrocarbyl radical of Formula C n H 2n+1 wherein n is a number ranging from 1 to 4.
  • C 1-4 alkyl groups comprise from 1 to 4 carbon atoms, preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbon atoms.
  • C 1-4 alkyl groups may be linear or branched and may be substituted as indicated herein. When a subscript is used herein following a carbon atom, the subscript refers to the number of carbon atoms that the named group may contain.
  • C 1-4 alkyl includes all linear, or branched alkyl groups with between 1 and 4 carbon atoms, and thus includes methyl, ethyl, n -propyl, i -propyl, 2-methyl-ethyl, butyl and its isomers (e.g. n -butyl, iso butyl and tert -butyl), and the like.
  • 'C 1-6 alkyl' as used herein as a group or part of a group represents a straight or branched chain saturated hydrocarbon radical having from 1 to 6 carbon atoms such as the groups defined for C 1-4 alkyl and n -pentyl, n -hexyl, 2-methylbutyl and the like.
  • Het 1a and Het 1b are carbon-linked oxetanyl (e.g. 3-oxetanyl), piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiolanyl, piperazinyl, tetrahydropyranyl and the like.
  • oxetanyl e.g. 3-oxetanyl
  • piperidinyl tetrahydrofuranyl
  • pyrrolidinyl tetrahydrofuranyl
  • thiolanyl thiolanyl
  • piperazinyl tetrahydropyranyl and the like.
  • Het 2c and Het 2d are carbon-linked oxetanyl (e.g. 3-oxetanyl), piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiolanyl, piperazinyl, tetrahydropyranyl, pyridinyl, furanyl, pyrizazinyl, thiazolyl, benzimidazolyl and the like; each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.
  • oxetanyl e.g. 3-oxetanyl
  • piperidinyl tetrahydrofuranyl
  • pyrrolidinyl tiolanyl
  • piperazinyl tetrahydropyranyl
  • pyridinyl furanyl
  • pyrizazinyl pyrizazinyl
  • thiazolyl benzimidazolyl and the
  • Het 2a and Het 2b are carbon- or nitrogen-linked oxetanyl, piperidinyl, tetrahydrofuranyl, pyrrolidinyl, thiolanyl, piperazinyl, tetrahydropyranyl, pyridinyl, furanyl, pyrizazinyl, thiazolyl, benzimidazolyl and the like; each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.
  • Non-limiting examples of R 8 and R 9 , or R 10 and R 11 , taken together to form a 4-, 5-, 6- or 7-membered saturated heterocyclyl are piperidinyl, azetidinyl, pyrrolidinyl, morpholinyl, hexahydro-1H-azepinyl; each of which may optionally be substituted, where possible, on carbon and/or nitrogen atoms according to any of the embodiments.
  • subject refers to an animal, preferably a mammal (e.g. cat, dog, primate or human), more preferably a human, who is or has been the object of treatment, observation or experiment.
  • a mammal e.g. cat, dog, primate or human
  • terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medicinal doctor or other clinician, which includes alleviation or reversal of the symptoms of the disease or disorder being treated.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
  • treatment is intended to refer to all processes wherein there may be a slowing, interrupting, arresting or stopping of the progression of a disease, but does not necessarily indicate a total elimination of all symptoms.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganisation of some of the bonding electrons.
  • R, S a particular configuration
  • any particular chiral atom is not specified in the structures shown herein, then all stereoisomers are contemplated and included as the compounds of the invention, either as a pure stereoisomer or as a mixture of two or more stereoisomers.
  • compound of Formula (I) is meant to include the stereoisomers thereof and the tautomeric forms thereof.
  • stereochemistry as mentioned in the previous paragraph, is specified by bonds which are shown as solid wedged or hashed wedged bonds, or are otherwise indicated as having a particular configuration (e.g. R, S ), then that stereoisomer is so specified and defined. It will be clear this also applies to subgroups of Formula (I).
  • Enantiomers are stereoisomers that are non-superimposable mirror images of each other.
  • a 1:1 mixture of a pair of enantiomers is a racemate or racemic mixture.
  • Atropisomers are stereoisomers which have a particular spatial configuration, resulting from a restricted rotation about a single bond, due to large steric hindrance. All atropisomeric forms of the compounds of Formula (I) are intended to be included within the scope of the present invention.
  • Diastereomers are stereoisomers that are not enantiomers, i.e. they are not related as mirror images.
  • Anomers are diastereoisomers of cyclic forms of sugars or similar molecules differing in the configuration at the anomeric carbon (C-1 atom of an aldose or the C-2 atom of a 2-ketose).
  • the cyclic forms of carbohydrates can exist in two forms, ⁇ - and ⁇ - based on the position of the substituent at the anomeric center.
  • Anomers are designated ⁇ if the configuration at the anomeric carbon is the same as that at the reference asymmetric carbon in a Fischer projection. If the configuration differs the anomer is designated ⁇ . For example, ⁇ -D-glucopyranose and ⁇ -D-glucopyranose, the two cyclic forms of glucose, are anomers.
  • the substituents may be in the E or the Z configuration.
  • Substituents on bivalent cyclic (partially) saturated radicals may have either the cis- or trans-configuration; for example if a compound contains a disubstituted cycloalkyl group, the substituents may be in the cis or trans configuration. Therefore, the invention includes enantiomers, atropisomers, diastereomers, racemates, E isomers, Z isomers, cis isomers, trans isomers and mixtures thereof, whenever chemically possible.
  • the absolute configuration is specified according to the Cahn-Ingold-Prelog system.
  • the configuration at an asymmetric atom is specified by either R or S.
  • Resolved stereoisomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • resolved enantiomers whose absolute configuration is not known can be designated by (+) or (-) depending on the direction in which they rotate plane polarized light.
  • stereoisomer is substantially free, i.e. associated with less than 50%, preferably less than 20%, more preferably less than 10%, even more preferably less than 5%, in particular less than 2% and most preferably less than 1%, of the other stereoisomers.
  • a compound of Formula (I) is for instance specified as (R)
  • a compound of Formula (I) is for instance specified as E
  • Z Z isomer
  • a compound of Formula (I) is for instance specified as cis, this means that the compound is substantially free of the trans isomer.
  • salts of the compounds of Formula (I) and solvates thereof are those wherein the counterion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • compositions of Formula (I) and solvates thereof are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of Formula (I) and solvates thereof, are able to form.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of Formula (I) and solvates thereof containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g.
  • primary, secondary and tertiary aliphatic and aromatic amines such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • the salt form can be converted by treatment with acid into the free acid form.
  • parenteral administration includes all forms of administration other than oral administration, in particular intravenous (IV), intramuscular (IM), and subcutaneous (SC) injection.
  • IV intravenous
  • IM intramuscular
  • SC subcutaneous
  • General information on prodrugs may be found e.g. in Bundegaard, H. "Design of Prodrugs” p. 1-92, Elsevier, New York-Oxford (1985 ).
  • solvate comprises the hydrates and solvent addition forms which the compounds of Formula (I) are able to form, as well as pharmaceutically acceptable addition salts thereof. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • the compounds of the invention as prepared in the processes described below may be synthesized in the form of mixtures of enantiomers, in particular racemic mixtures of enantiomers, that can be separated from one another following art-known resolution procedures.
  • a manner of separating the enantiomeric forms of the compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • the present invention also embraces isotopically-labeled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature).
  • isotopes and isotopic mixtures of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 122 I, 123 I, 125 I, 131 I, 75 Br, 76 Br, 77 Br and 82 Br.
  • the radioactive isotope is selected from the group of 2 H, 3 H, 11 C and 18 F. More preferably, the radioactive isotope is 2 H.
  • deuterated compounds are intended to be included within the scope of the present invention.
  • Certain isotopically-labeled compounds of the present invention are useful in compound and for substrate tissue distribution assays.
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Positron emitting isotopes such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • the present invention concerns novel compounds of Formula (I), wherein
  • the present invention concerns novel compounds of Formula (I), wherein
  • the present invention concerns novel compounds of Formula (I), wherein
  • the present invention concerns novel compounds of Formula (I), wherein
  • the present invention concerns novel compounds of Formula (I), wherein
  • Another embodiment of the present invention relates to those compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:
  • the present invention concerns novel compounds of Formula (I), wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (I-1): wherein all variables are defined as for compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
  • the present invention concerns novel compounds of Formula (1-1) wherein
  • Another embodiment of the present invention relates to those compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein one or more of the following restrictions apply:
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R a and R b represent hydrogen.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (I-1) wherein R 8 and R 9 are always linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (I-1), wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), and wherein R 8 and R 9 are always linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (1-2): wherein all variables are defined as for compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (1-2) wherein R 8 and R 9 are always linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 8 and R 9 are always linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (1-3) wherein all variables are defined as for compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (I-3a) wherein all variables are defined as for compounds of Formula (I) or any subgroup thereof as mentioned in any of the other embodiments.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (I-3a) wherein R 8 and R 9 are always linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (1-3) and wherein at least one of the dotted lines represents an additional bond.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein the compounds of Formula (I) are restricted to the compounds of Formula (I-3a) wherein R 8 and R 9 are always linked together, and wherein at least one of the dotted lines represents an additional bond.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein at least one of the dotted lines, where possible, represent an additional bond.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X 3 represents N.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X 3 represents C or CH.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 10 and R 11 , or R 8 and R 9 are linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), and wherein R 8 and R 9 are always linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1), and wherein R 10 and R 11 or R 8 and R 9 are linked together.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein X 1 represents a covalent bond.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein all 4-, 5-, 6- or 7-membered saturated heterocyclyls are restricted to 5-, 6- or 7-membered saturated heterocyclyls, each of which may be optionally substituted according to any of the other embodiments;
  • X 1 represents a covalent bond; and Het represents (a-1).
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Y represents -CH 2 - or -CF 2 -; in particular wherein Y represents -CH 2 -.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein maximum one of Q 1 and Q 2 represents N.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Q 1 represents CR 14a ; and Q 2 represents CR 14b ; in particular wherein Q 1 represents CH; and Q 2 represents CH.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); Q 1 represents CR 14a ; and Q 2 represents CR 14b ; in particular wherein Q 1 represents CH; and Q 2 represents CH.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 1 and R 2 represent hydrogen; and Y represents -O-.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R a and R b represent hydrogen; and Y represents -O-.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R a and R b represent hydrogen; R 1 and R 2 represent hydrogen; and Y represents -O-.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2).
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).
  • the present invention relates to any one of the compounds of Formula (I-1), (I-2), (I-3) or (I-3a), wherein Het represents a bicyclic aromatic heterocyclic ring system selected from the group consisting of (a-1) and (a-2), in particular wherein Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 1 and R 2 represent hydrogen.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 1 and R 2 represent hydrogen; Y represents -O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R a and R b represent hydrogen; Y represents -O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R a and R b represent hydrogen; R 1 and R 2 represent hydrogen; Y represents -O-; and Het represents a bicyclic aromatic heterocyclic ring system of Formula (a-1).
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3a , R 3c , R 3b represent hydrogen; and R 4a , R 4c , R 4b represent hydrogen, halo, or C 1-4 alkyl; in particular R 4a , R 4c , R 4b represent halo, or C 1-4 alkyl.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3a , R 3c , R 3b represent hydrogen, when R 4a , R 4c , R 4b are different from hydrogen.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 4a , R 4c , R 4b represent hydrogen, when R 3a , R 3c , R 3b are different from hydrogen.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 7a and R 7b represent hydrogen.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het represents (a-1); R 3a represents -NR 12a R 12b ; and R 12a and R 12b represent hydrogen.
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3a , R 3b and R 3c represent other than halo. In an embodiment, the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein R 3a , R 3b and R 3c represent -NH 2 .
  • the present invention relates to those compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup thereof as mentioned in any of the other embodiments, wherein Het 2a , Het 2b , Het 2c and Het 2d are aromatic.
  • the present invention relates to a subgroup of Formula (I) as defined in the general reaction schemes.
  • the compound of Formula (I) is selected from the group consisting of compounds 19, 29, 74, 94, 95a, 95b, 101, 107, 108, 166, 167, 178, 179, 181, 206 and 207.
  • the compound of Formula (I) is selected from the group consisting of compounds 19, 29, 74, 94, 95a, 95b, 101, 107, 108, 166, 167, 178, 179, 181, 206 and 207, and pharmaceutically acceptable addition salts, the free bases, and solvates thereof.
  • the compound of Formula (I) is selected from the group consisting of any of the exemplified compounds, and the free bases, the pharmaceutically acceptable addition salts, and the solvates thereof.
  • compounds of the present invention may also be prepared by analogous reaction protocols as described in the general schemes below, combined with standard synthetic processes commonly used by those skilled in the art of organic chemistry.
  • reaction work-up refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
  • microwave heating may be used instead of conventional heating to shorten the overall reaction time.
  • a primary or secondary amine group may be reductively alkylated by reaction with an aldehyde or a keton in the presence of a suitable reducing reagent such as for example sodium triacetoxyborohydride (NaBH(AcO) 3 ) together with a suitable solvent such as for example DCM at a suitable temperature such as for example room temperature; or alternatively in the presence of NaBH 3 CN together with a suitable solvent such as for example MeOH at a suitable temperature such as for example between room temperature and 50 °C.
  • a suitable reducing reagent such as for example sodium triacetoxyborohydride (NaBH(AcO) 3 ) together with a suitable solvent such as for example DCM at a suitable temperature such as for example room temperature
  • a suitable solvent such as for example MeOH
  • the starting materials is available as a salt form
  • a base such as for example N,N-diisopropylethylamine (DIPEA).
  • DIPEA N,N-diisopropylethylamine
  • 'LG 1 ' is defined as a leaving group such as halogen
  • 'LG 2 ' is defined as leaving group such as halogen or -SCH 3
  • 'LG 3 ' is defined as leaving group such as halogen or -SCH 3 . All other variables in Scheme 1 are defined according to the scope of the present invention.
  • 'LG 1 ' is defined as a leaving group such as halogen
  • 'LG 2 ' is defined as leaving group such as halogen or -SCH 3
  • 'LG 3 ' is defined as leaving group such as halogen or -SCH 3 . All other variables in Scheme 4 are defined according to the scope of the present invention.
  • the skilled person will realize that the intermediates of Formula VII-a, IX-a and XI-a can be further reacted in an analogous reaction protocol as described in Scheme 4 to obtain the corresponding final compounds.
  • reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography.
  • the chirally pure forms of the compounds of Formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates and their salt forms are particularly useful in the preparation of chirally pure compounds of Formula (I). Also enantiomeric mixtures of the intermediates are useful in the preparation of compounds of Formula (I) with the corresponding configuration.
  • the compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries and the like.
  • diseases such as a blood disorder, metabolic disorders, autoimmune disorders, cancer, inflammatory diseases, cardiovascular diseases, neurodegenerative diseases, pancreatitis, multiorgan failure, kidney diseases, platelet aggregation, sperm motility, transplantation rejection, graft rejection, lung injuries and the like.
  • the compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as allergy, asthma, hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorder, diabetes, obesity, blood disorder, sickle cell anemia, and the like.
  • diseases such as allergy, asthma, hematopoietic cancer, lung cancer, prostate cancer, melanoma, metabolic disorder, diabetes, obesity, blood disorder, sickle cell anemia, and the like.
  • the compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as a proliferative disorder, such as an autoimmune disease, cancer, a benign neoplasm, or an inflammatory disease.
  • diseases such as a proliferative disorder, such as an autoimmune disease, cancer, a benign neoplasm, or an inflammatory disease.
  • the compounds according to the present invention or pharmaceutical compositions thereof may be useful for treating or preventing, in particular treating, of diseases such as a metabolic disorder comprising diabetes, obesity; a proliferative disorder comprising cancer, hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer; blood disorder; hemoglobinopathy; sickle cell anemia; ⁇ -thalessemia, an inflammatory disease, and autoimmune disease e.g. rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, diarrhea, gastroesophageal reflux disease, and the like.
  • diseases such as a metabolic disorder comprising diabetes, obesity; a proliferative disorder comprising cancer, hematopoietic cancer, lung cancer, prostate cancer, melanoma, or pancreatic cancer; blood disorder; hemoglobinopathy; sickle cell anemia; ⁇ -thalessemia, an inflammatory disease, and autoimmune disease e.g. rheumato
  • the inhibition of PRMT5 by a provided compound may be useful in treating or preventing, in particular treating, the following non-limiting list of cancers: breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous cystadenoma.
  • cancers breast cancer, lung cancer, esophageal cancer, bladder cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma,
  • metabolic disorders which may be treated or prevented, in particular treated, include, but are not limited to, diabetes or obesity.
  • blood disorders which may be treated or prevented, in particular treated, include, but are not limited to, hemoglobinopathy, such as sickle cell disease or ⁇ -thalassemia.
  • cancers which may be treated or prevented, in particular treated, include, but are not limited to, acoustic neuroma, adenocarcinoma, adrenal gland cancer, anal cancer, angiosarcoma (e.g., lymphangio sarcoma, lymphangioendothelio sarcoma, hemangio sarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer (e.g., cervical adenocarcinom
  • uterine cancer uterine sarcoma
  • esophageal cancer e.g., adenocarcinoma of the esophagus, Barrett's adenocarinoma
  • eye cancer e.g., intraocular melanoma, retinoblastoma
  • familiar hypereosinophilia gall bladder cancer
  • gastric cancer e.g., stomach adenocarcinoma
  • gastrointestinal stromal tumor GIST
  • head and neck cancer e.g., head and neck squamous cell carcinoma
  • oral cancer e.g., oral squamous cell carcinoma (OSCC)
  • throat cancer e.g., pharyngeal cancer, laryngeal cancer, nasopharyngeal cancer, oropharyngeal cancer
  • hematopoietic cancers e.g., leukemia such as acute lymphocytic leukemia (ALL)
  • ALL acute lymphocy
  • alpha chain disease e.g., alpha chain disease, gamma chain disease, mu chain disease
  • hemangioblastoma e.g., hemangioblastoma a.k.a.
  • MMD myeloproliferative disorder
  • MPD
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget' s disease of the
  • neurodegenerative diseases which may be treated or prevented, in particular treated, include, but are not limited to, motor neurone disease, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, Alzheimer's disease, AIDS-related dementia, Parkinson's disease, amyotropic lateral sclerosis, retinitis pigmentosa, spinal muscular atropy, and cerebellar degeneration.
  • cardiovascular diseases which may be treated or prevented, in particular treated, include, but are not limited to, cardiac hypertrophy, restenosis, atherosclerosis, and glomerulonephritis.
  • inflammatory diseases which may be treated or prevented, in particular treated, include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), rhinitis, asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), upper respiratory tract disease, ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, diverticulitis, cermatomyositis
  • prostatitis chronic inflammation associated with cranial radiation injury, pelvic inflammatory disease, reperfusion injury, regional enteritis, rheumatic fever, systemic lupus erythematosus, schleroderma, scierodoma, sarcoidosis, spondyloarthopathies, Sjogren's syndrome, thyroiditis, transplantation rejection, tendonitis, trauma or injury (e.g. , frostbite, chemical irritants, toxins, scarring, burns, physical injury), vasculitis, vitiligo and Wegener's granulomatosis.
  • trauma or injury e.g. , frostbite, chemical irritants, toxins, scarring, burns, physical injury
  • vasculitis vitiligo and Wegener's granulomatosis.
  • the inflammatory disease is an acute inflammatory disease (e.g., for example, inflammation resulting from infection).
  • the inflammatory disease is a chronic inflammatory disease (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds may also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • the compounds may also be useful in treating inflammation associated with cancer.
  • autoimmune diseases which may be treated or prevented, in particular treated, include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, amyotrophic lateral sclerosis, amylosis, multiple sclerosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, eczema hypersensitivity reactions, burns, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (
  • eosinophilic gastrointestinal disorders e.g., eosinophilic esophagitis, eosinophilic gastritis, eosinophilic gastroenteritis, eosinophilic colitis
  • gastritis diarrhea, gastroesophageal reflux disease (GORD, or its synonym GERD
  • IBD inflammatory bowel disease
  • IBS inflammatory bowel syndrome
  • disorders ameliorated by a gastroprokinetic agent e.g.
  • GORD gastroesophageal reflux disease
  • GERD gastroesophageal reflux disease
  • eosinophilic esophagitis gastroparesis such as diabetic gastroparesis
  • food intolerances and food allergies and other functional bowel disorders such as non-ulcerative dyspepsia (NUD) and non-cardiac chest pain (NCCP, including costo-chondritis)
  • a provided compound may be useful in somatic cell reprogramming, such as reprogramming somatic cells into stem cells.
  • a provided compound may be useful in germ cell development, and are thus envisioned useful in the areas of reproductive technology and regenerative medicine.
  • diseases which may be treated or prevented, in particular treated include, but are not limited to, ischemic injury associated myocardial infarctions, immunological diseases, stroke, arrhythmia, toxin-induced or alcohol related liver diseases, aspirin-sensitive rhinosinusitis, cystic fibrosis, cancer pain, and haematological diseases, for example chronic anemia and aplastic anemia.
  • the compounds of the present invention may also have therapeutic applications in sensitising tumour cells for radiotherapy and chemotherapy.
  • the compounds of the present invention may be used as "radiosensitizer” and/or “chemosensitizer” or can be given in combination with another “radiosensitizer” and/or “chemosensitizer”.
  • radiosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of the cells to ionizing radiation and/or to promote the treatment of diseases which are treatable with ionizing radiation.
  • chemosensitizer is defined as a molecule, preferably a low molecular weight molecule, administered to animals in therapeutically effective amounts to increase the sensitivity of cells to chemotherapy and/or promote the treatment of diseases which are treatable with chemotherapeutics.
  • hypoxic cell radiosensitizers e.g., 2- nitroimidazole compounds, and benzotriazine dioxide compounds
  • non-hypoxic cell radiosensitizers e.g., halogenated pyrimidines
  • various other potential mechanisms of action have been hypothesized for radiosensitizers in the treatment of disease.
  • radiosensitizers include, but are not limited to, the following: metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5- iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and therapeutically effective analogs and derivatives of the same.
  • Photodynamic therapy (PDT) of cancers employs visible light as the radiation activator of the sensitizing agent.
  • photodynamic radiosensitizers include the following, but are not limited to: hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tin etioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs and derivatives of the same.
  • Radiosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of radiosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour with or without additional radiation; or other therapeutically effective compounds for treating cancer or other diseases.
  • Chemosensitizers may be administered in conjunction with a therapeutically effective amount of one or more other compounds, including but not limited to: compounds which promote the incorporation of chemosensitizers to the target cells; compounds which control the flow of therapeutics, nutrients, and/or oxygen to the target cells; chemotherapeutic agents which act on the tumour or other therapeutically effective compounds for treating cancer or other disease.
  • Calcium antagonists for example verapamil, are found useful in combination with antineoplastic agents to establish chemo sensitivity in tumor cells resistant to accepted chemotherapeutic agents and to potentiate the efficacy of such compounds in drug-sensitive malignancies.
  • the compounds of the present invention might also reduce the risk of cancer recurrence.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for use as a medicament.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the inhibition of PRMT5 activity.
  • the compounds of the present invention can be "anti-cancer agents", which term also encompasses “anti-tumor cell growth agents” and “anti-neoplastic agents”.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for use in the treatment of diseases mentioned above.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular for the treatment, of said diseases.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the treatment or prevention, in particular in the treatment, of PRMT5 mediated diseases or conditions.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the inhibition of PRMT5.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment or prevention, in particular for the treatment, of any one of the disease conditions mentioned hereinbefore.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, for the manufacture of a medicament for the treatment of any one of the disease conditions mentioned hereinbefore.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, can be administered to mammals, preferably humans, for the treatment or prevention of any one of the diseases mentioned hereinbefore.
  • Said methods comprise the administration, i.e. the systemic or topical administration, preferably oral administration, of an effective amount of a compound of Formula (I) or a pharmaceutically acceptable addition salt, or a solvate thereof, to warm-blooded animals, including humans.
  • An effective therapeutic daily amount would be from about 0.005 mg /kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
  • a particular effective therapeutic daily amount might be from about 0.01 to 1.00 g twice a day (BID), more in particular 0.30 to 0.85 g BID; even more in particular 0.40 g BID.
  • BID twice a day
  • the amount of a compound according to the present invention, also referred to here as the active ingredient, which is required to achieve a therapeutically effect will of course, vary on case-by-case basis, for example with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a method of treatment may also include administering the active ingredient on a regimen of between one and four intakes per day.
  • the compounds according to the invention are preferably formulated prior to administration.
  • suitable pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients.
  • the compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents.
  • Combination therapy includes administration of a single pharmaceutical dosage formulation which contains a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and one or more additional therapeutic agents, as well as administration of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and each additional therapeutic agents in its own separate pharmaceutical dosage formulation.
  • a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and a therapeutic agent may be administered to the patient together in a single oral dosage composition such as a tablet or capsule, or each agent may be administered in separate oral dosage formulations.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition.
  • the present invention further provides a pharmaceutical composition and, as active ingredient, a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof.
  • the carrier or diluent must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipients thereof.
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • the compounds according to the invention in particular the compounds of Formula (I) and pharmaceutically acceptable addition salts, and solvates thereof, or any subgroup or combination thereof may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • compositions of this invention an effective amount of the particular compound as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, in particular, for administration orally, rectally, percutaneously, by parenteral injection or by inhalation.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, diluents, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable solutions containing a compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, may be formulated in an oil for prolonged action.
  • Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment. Acid or base addition salts of compounds of Formula (I) due to their increased water solubility over the corresponding base or acid form, are more suitable in the preparation of aqueous compositions.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, suppositories, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • ⁇ -, ⁇ - or ⁇ -cyclodextrins or their derivatives in particular hydroxyalkyl substituted cyclodextrins, e.g. 2-hydroxypropyl- ⁇ -cyclodextrin or sulfobutyl- ⁇ -cyclodextrin.
  • co-solvents such as alcohols may improve the solubility and/or the stability of the compounds according to the invention in pharmaceutical compositions.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99 % by weight, more preferably from 0.1 to 70 % by weight, even more preferably from 0.1 to 50 % by weight of the compound of Formula (I), a pharmaceutically acceptable addition salt, or a solvate thereof, and from 1 to 99.95 % by weight, more preferably from 30 to 99.9 % by weight, even more preferably from 50 to 99.9 % by weight of a pharmaceutically acceptable carrier, all percentages being based on the total weight of the composition.
  • a combination of a compound of the present invention with another anticancer agent is envisaged, especially for use as a medicine, more specifically for use in the treatment of cancer or related diseases.
  • the compounds of the invention may be advantageously employed in combination with antibody based immune cell redirection, for example T-cell/neutrophil redirection. This can be achieved for example by the use of bispecific monoclonal antibodies or artificial T-cell receptors.
  • the compounds of the invention may be advantageously employed in combination with one or more other medicinal agents, more particularly, with other anti-cancer agents or adjuvants in cancer therapy.
  • anti-cancer agents or adjuvants supporting agents in the therapy
  • the present invention further relates to a product containing as first active ingredient a compound according to the invention and as further active ingredient one or more anticancer agents, as a combined preparation for simultaneous, separate or sequential use in the treatment of patients suffering from cancer.
  • the one or more other medicinal agents and the compound according to the present invention may be administered simultaneously (e.g. in separate or unitary compositions) or sequentially in either order. In the latter case, the two or more compounds will be administered within a period and in an amount and manner that is sufficient to ensure that an advantageous or synergistic effect is achieved.
  • the preferred method and order of administration and the respective dosage amounts and regimes for each component of the combination will depend on the particular other medicinal agent and compound of the present invention being administered, their route of administration, the particular tumour being treated and the particular host being treated.
  • the optimum method and order of administration and the dosage amounts and regime can be readily determined by those skilled in the art using conventional methods and in view of the information set out herein.
  • the weight ratio of the compound according to the present invention and the one or more other anticancer agent(s) when given as a combination may be determined by the person skilled in the art. Said ratio and the exact dosage and frequency of administration depends on the particular compound according to the invention and the other anticancer agent(s) used, the particular condition being treated, the severity of the condition being treated, the age, weight, gender, diet, time of administration and general physical condition of the particular patient, the mode of administration as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that the effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. A particular weight ratio for the present compound of Formula (I) and another anticancer agent may range from 1/10 to 10/1, more in particular from 1/5 to 5/1, even more in particular from 1/3 to 3/1.
  • the platinum coordination compound is advantageously administered in a dosage of 1 to 500mg per square meter (mg/m 2 ) of body surface area, for example 50 to 400 mg/m 2 , particularly for cisplatin in a dosage of about 75 mg/m 2 and for carboplatin in about 300mg/m 2 per course of treatment.
  • the taxane compound is advantageously administered in a dosage of 50 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 75 to 250 mg/m 2 , particularly for paclitaxel in a dosage of about 175 to 250 mg/m 2 and for docetaxel in about 75 to 150 mg/m 2 per course of treatment.
  • the camptothecin compound is advantageously administered in a dosage of 0.1 to 400 mg per square meter (mg/m 2 ) of body surface area, for example 1 to 300 mg/m 2 , particularly for irinotecan in a dosage of about 100 to 350 mg/m 2 and for topotecan in about 1 to 2 mg/m 2 per course of treatment.
  • the anti-tumour podophyllotoxin derivative is advantageously administered in a dosage of 30 to 300 mg per square meter (mg/m 2 ) of body surface area, for example 50 to 250mg/m 2 , particularly for etoposide in a dosage of about 35 to 100 mg/m 2 and for teniposide in about 50 to 250 mg/m 2 per course of treatment.
  • the anti-tumour vinca alkaloid is advantageously administered in a dosage of 2 to 30 mg per square meter (mg/m 2 ) of body surface area, particularly for vinblastine in a dosage of about 3 to 12 mg/m 2 , for vincristine in a dosage of about 1 to 2 mg/m 2 , and for vinorelbine in dosage of about 10 to 30 mg/m 2 per course of treatment.
  • the anti-tumour nucleoside derivative is advantageously administered in a dosage of 200 to 2500 mg per square meter (mg/m 2 ) of body surface area, for example 700 to 1500 mg/m 2 , particularly for 5-FU in a dosage of 200 to 500mg/m 2 , for gemcitabine in a dosage of about 800 to 1200 mg/m 2 and for capecitabine in about 1000 to 2500 mg/m 2 per course of treatment.
  • the alkylating agents such as nitrogen mustard or nitrosourea is advantageously administered in a dosage of 100 to 500 mg per square meter (mg/m 2 ) of body surface area, for example 120 to 200 mg/m 2 , particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m 2 , for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustine in a dosage of about 150 to 200 mg/m 2 , and for lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • mg/m 2 body surface area
  • cyclophosphamide in a dosage of about 100 to 500 mg/m 2
  • chlorambucil in a dosage of about 0.1 to 0.2 mg/kg
  • carmustine in a dosage of about 150 to 200 mg/m 2
  • lomustine in a dosage of about 100 to 150 mg/m 2 per course of treatment.
  • the anti-tumour anthracycline derivative is advantageously administered in a dosage of 10 to 75 mg per square meter (mg/m 2 ) of body surface area, for example 15 to 60 mg/m 2 , particularly for doxorubicin in a dosage of about 40 to 75 mg/m 2 , for daunorubicin in a dosage of about 25 to 45 mg/m 2 , and for idarubicin in a dosage of about 10 to 15 mg/m 2 per course of treatment.
  • the antiestrogen agent is advantageously administered in a dosage of about 1 to 100 mg daily depending on the particular agent and the condition being treated.
  • Tamoxifen is advantageously administered orally in a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Toremifene is advantageously administered orally in a dosage of about 60 mg once a day, continuing the therapy for sufficient time to achieve and maintain a therapeutic effect.
  • Anastrozole is advantageously administered orally in a dosage of about 1mg once a day.
  • Droloxifene is advantageously administered orally in a dosage of about 20-100 mg once a day.
  • Raloxifene is advantageously administered orally in a dosage of about 60 mg once a day.
  • Exemestane is advantageously administered orally in a dosage of about 25 mg once a day.
  • Antibodies are advantageously administered in a dosage of about 1 to 5 mg per square meter (mg/m 2 ) of body surface area, or as known in the art, if different.
  • Trastuzumab is advantageously administered in a dosage of 1 to 5 mg per square meter (mg/m 2 ) of body surface area, particularly 2 to 4mg/m 2 per course of treatment. These dosages may be administered for example once, twice or more per course of treatment, which may be repeated for example every 7, 14, 21 or 28 days.
  • rt or "r.t.” means room temperature; "Me” means methyl; “MeOH” means MeOH; “Et” means ethyl; “EtOH” means ethanol; “HMPA” means hexamethylphosphorous triamide; “TosOH” means 4-methylbenzenesulfonic acid; "NaBH(AcO) 3 " or “NaBH(OAc) 3 " means sodium triacetoxyborohydride; "EtOAc” means ethyl acetate; “Et 3 N” means triethylamine; “DCM” means dichloromethane; “q.s.” means quantum sufficit; "Int.” Means intermediate; "ACN” means acetonitrile; “DMF” means N,N- dimethyl formamide; “THF” means tetrahydrofuran; 'iPrOH” means 2-propanol; “LC” means liquid chromatography; “LCMS” means Liquid Chromatography
  • the typical concentration of ammonia in MeOH used in the reactions below, is 7 N.
  • reaction mixture was then stirred at 50°C for 2 hours.
  • the reaction mixture was cooled to 25°C and NaHCO 3 (14 g, 100 mmol) was added slowly.
  • Ethyl acetate 230 mL was added, followed by the addition of a half-saturated NaHCO 3 solution.
  • the organic phase was isolated and the aqueous phase was extracted with ethyl acetate (two times 230 mL).
  • the combined organic phase was dried with anhydrous MgSO 4 , filtered and concentrated to afford intermediate 13 as yellow solid (17.40 g, quantitative yield in 2 steps).
  • the crude product was directly used as such in the next reaction step without further purification.
  • intermediate 15 (1.8 g, 5 mmol) in 1,4-dioxane (30 mL) was added NH 3 .H 2 O (30 mL). The reaction mixture was heated to 80°C for 12 hours in a sealed tube. The mixture was cooled to room temperature and the solvent was evaporated in vacuum affording intermediate 28 (1.8 g, 98% yield) as yellow oil.
  • N,N'-diphenylethylenediamine (28.8 g, 0.14 mol) was added to the combined filtrate and washings and the resulting solution was stored at room temperature for 1 hour. Water was then added to slight turbidity and the solid was filtered. The filtrate was partitioned between water and chloroform and the organic phase was washed twice with water, dried over MgSO 4 and evaporated. The solid and the residue of organic phase were recrystallized in ethanol to give intermediate 44 (34.79g, 47.8 mmol, 40% yield).
  • reaction mixture was stirred for 10 minutes and then a solution of intermediate 29 (0.55 g, 1.7 mmol) in DCM (8 mL) was added dropwise. After addition the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered over a pad of Celite. The pad was washed three times with DCM. The solvents of the filtrate were evaporated. The residue was dissolved in DCM, washed two times with a saturated aqueous NaHCO 3 solution, washed with brine, dried with MgSO 4 , filtered and the solvents of the filtrate evaporated.
  • Lithium aluminum hydride (0.765 mL, 0.765 mmol, 1M in THF) was added dropwise to a stirred solution of intermediate 143 (104 mg, 0.19 mmol) in THF (4 mL, anhydrous) at 0°C and under nitrogen atmosphere. After addition the reaction mixture was stirred at 0°C for 10 minutes. The reaction was cooled to 0°C and then quenched with water. MeOH was added and the resulting suspension was filtered. The residue was washed with MeOH. The combined solvents of the filtrate were evaporated.
  • Methanesulfonyl chloride (0.078 mL, 1.0 mmol) was added dropwise to a stirred solution of intermediate 180 (173 mg, 0.39 mmol) and Et 3 N (0.14 mL, 1.0 mmol) in DCM (5 mL) at 0°C. After addition the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and then an additional amount of Et 3 N (0.28 mL, 2.0 mmol) was added followed by the addition of methanesulfonyl chloride (0.16 mL, 2.0 mmol). The reaction mixture was stirred at 0°C for 1 hour.
  • the residue was purified over a SiO 2 column, type Grace Reveleris SRC, 80 g, Si 40, on a Grace Reveleris X2 purification system using dichlormethane and MeOH as eluens in a gradient starting from 100% DCM to 25% MeOH and 75% DCM.
  • the fractions containing product were combined and the solvents were evaporated yielding 10.5 g crude intermediate 327.
  • the combined water layers were extracted again three times with DCM with some MeOH.
  • the combined organic layer was dried (MgSO 4 ), filtered and the solvents of the filtrate evaporated yielding 6.62 g crude intermediate 327.
  • the water layer was evaporated yielding 12.3 g crude intermediate 327.
  • the three crude fractions were combined and purified over a SiO 2 column, type Grace Reveleris SRC, 120 g, Si 40, on a Grace Reveleris X2 purification system with a solid sample loader using DCM and MeOH as eluens in a gradient starting from 100% DCM to 25% MeOH and 75% DCM.
  • the fractions containing product were combined and the solvents were evaporated yielding 18.1 g of pure intermediate 327 (yield: 72.7 %).
  • the reaction mixture was purified by preparative HPLC (Column: Phenomenex Synergi C18 150 ⁇ 30mm, 4um; Mobile phase: from 29% MeCN in water to 59% MeCN in water, 0.1% TFA; Gradient Time: 8 min; Flow Rate: 30 ml/min; Wavelength: 220 nm).
  • the fractions contain desired product were combined and lyophilized to afford intermediate 350 (180 mg, 260 ⁇ mol, 69.5% yield) as pale yellow solid.
  • the crude final compound 95a fraction 1 was dissolved in DCM and purified over a SiO2 column, type Grace Reveleris SRC, 120 g, Si 40, on a Grace Reveleris X2 purification system using DCM and MeOH as eluens in a gradient starting from 100% DCM to 40% MeOH and 60% DCM..
  • the fractions containing product were combined and the solvents were evaporated yielding 4.55 g crude final compound 95a fraction 2 and 5.43 g crude final compound 95a fraction 3.
  • Fraction crude final compound 96fraction 1 was dissolved in DCM and purified over a SiO 2 column, type Grace Reveleris SRC, 80 g, Si 40, on a Grace Reveleris X2 purification system using DCM and MeOH as eluens in a gradient starting from 100% DCM to 40% MeOH and 60% DCM. The fractions containing product were combined and the solvents were evaporated yielding 0.46 g. A mixture of 70 % final compound 96 as a free base and 30% final compound 97 as a free base.
  • the crude mixture of final compounds 99 and 100 were dissolved in DCM and purified over a SiO 2 column, type Grace Reveleris SRC, 80 g, Si 40, on a Armen Spot II Ultimate purification system using DCM and MeOH as eluens in a gradient starting from 100% DCM for 5 CV's and ending with 20% MeOH and 80% DCM over 15 CV's.
  • the fractions containing product were combined and the solvents were evaporated yielding 1.41 g of a mixture of 65 % final compound 99 and 35% final compound 100 as mono HCl salt.
  • the filtrate of pure final compound 103 fraction2 was evaporated, dissolved in DCM and washed three times with a saturated aqeous NaHCO 3 solution to obtain the product as free base after separation of the organic layer, drying with MgSO 4 and evaporating off the solvents.
  • the residue was dissolved in a mixture of 200 mL DIPE and 25 mL ACN and then acidified with 1 equivalent of HCl using a 2M solution of HCl in Et 2 O.
  • the formed white precipitate was filtered off, washed with DIPE and dried.
  • the resulting solid material was recrystallized in 40 mL ACN.
  • the precipitate was filtered off and dried in vacuo at 45°C yielding 196.2 mg pure final compound 103 fraction3 as bis HCl salt .
  • NaBH(OAc)3 (432.182 mg, 2.039 mmol) was added to a solution of a mixture of final compound 166 and final compound 167 (391 mg, 1 mmol), formaldehyde (0.107 mL, 1.43 mmol), AcOH (0.058 mL, 1 mmol) in MeOH (22mL). The solution was stirred at room temperature for 2h. Again NaBH(OAc) 3 (216mg, 1 mmol) was added to the solution and the reaction was stirred overnight. Again NaBH(OAc) 3 (216 mg, 1 mmol) and formaldehyde (0.038 mL, 0.5mmol were added to the solution and the reaction was stirred overnight.
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • tune parameters e.g. scanning range, dwell time
  • ions allowing the identification of the compound's nominal monoisotopic molecular weight (MW).
  • Data acquisition was performed with appropriate software.
  • Compounds are described by their experimental retention times (R t ) and ions. If not specified differently in the table of data, the reported molecular ion corresponds to the [M+H] + (protonated molecule) and/or [M-H] - (deprotonated molecule).
  • the type of adduct is specified (i.e.
  • SQL Single Quadrupole Detector
  • MSD Mass Selective Detector
  • RT r.t.
  • BEH bridged ethylsiloxane/silica hybrid
  • DAD Diode Array Detector
  • HSS High Strength silica.
  • Q-Tof Quadrupole Time-of-flight mass spectrometers
  • CLND ChemiLuminescent Nitrogen Detector
  • ELSD Evaporative Light Scanning Detector
  • Values are peak values, and are obtained with experimental uncertainties that are commonly associated with this analytical method.
  • melting points were determined with a DSC823e (Mettler-Toledo). Melting points were measured with a temperature gradient of 10°C/minute. Maximum temperature was 300°C. Co 183: 132.73 °C
  • m.p. were determined in open capillary tubes on a Mettler Toledo MP50 apparatus. M.p. were measured with a temperature ranging from 50°C to 300°C, using a gradient of 10 °C/minute. The m.p. value was read from a digital display.
  • PRMT5-MEP50 enzyme was purchased from Charles River (Argenta). The enzyme complex was produced in insect cells (Sf9) infected simultaneously with two baculoviruses. One virus expresses full length human PRMT5 with Flag-tag at N-terminus, the second virus expresses full length MEP50 with His6-TEV cleavage at N-terminus. The protein was affinity purified using anti-Flag (M2) beads eluted with 3xFLAG peptide, followed by His-Select eluted with 0.5M imidazole. Eluted protein was then dialysed against tris-buffered saline (TBS) (pH 8.0) containing 20% glycerol and 3mM dithiothreitol (DTT).
  • TSS tris-buffered saline
  • DTT dithiothreitol
  • High Throughput Mass Spectrometer Assay PRMT5 catalyzes the sequential methylations of the terminal nitrogen atoms on the guanidine groups of arginine residues within proteins using co-substrate S-adenosyl-L-methionine (AdoMet, SAM), forming mono-methyl (MMA), symmetric-dimethyl arginine (sDMA) and S-adenosyl-L-homocysteine (AdoHcy, SAH).
  • the enzyme activity was determined by following the product SAH formation using high throughput mass spectrometry (Agilent Rapidfire 300 System coupled to a Sciex 4000 series QTrap® triple-quad MS/MS).
  • the reaction buffer was 20 mM Tris-HCl, pH 8.5, 50 mM NaCl, 5 mM MgCl 2 and 1 mM DTT. The reaction activity was stopped using 1% formic acid (final concentration).
  • IC 50 Studies were performed using eleven point dosing series made for each compound by serially diluted 1:2 in dimethyl sulfoxide (DMSO), with point 12 being a DMSO control.
  • Compounds were first spotted to plates, and followed by addition of 2 ⁇ M SAM and 0.6 ⁇ M H2A (histone H2A) solution mixture. The same volume of enzyme solution was added to initiate the enzymatic reactions. The final concentrations of the reaction are at 1 ⁇ M SAM, 0.3 ⁇ M H2A and 10 nM enzyme. The reaction was incubated at 30 °C for 60 minutes (min) and then quenched by addition of formic acid to a final concentration of 1%.
  • DMSO dimethyl sulfoxide
  • A549 cells (ATCC, Cat # CCL-185) were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Sigma, Cat #D5796), supplemented with 10% Fetal Calf Serum (FCS) (HyCloneTM, Cat #SV30160.03), 100 mM Sodium Pyruvate (Sigma, Cat #S8636), 200 mM L-Glutamine (Sigma, Cat #G7513) and 50 mg/mL Gentamycing (Gibco, Cat #15750-037).
  • DMEM Dulbecco's Modified Eagle's Medium
  • FCS Fetal Calf Serum
  • HyCloneTM HyCloneTM, Cat #SV30160.03
  • 100 mM Sodium Pyruvate Sigma, Cat #S8636
  • 200 mM L-Glutamine Sigma, Cat #G7513
  • 50 mg/mL Gentamycing (Gibco, Cat #15750-037).
  • DPBS Dulbecco's phosphate buffered saline
  • PBS phosphate buffered saline
  • 10X phosphate buffered saline
  • Formalin solution 10% Sigma, HT50-1-128-4L
  • MeOH 100% Sigma, Cat #32213-2.5L
  • Triton X-100 Acros, Cat #215680010
  • Bovine Serum Albumin BSA
  • Alexa fluor 488 goat anti-rabbit antibody HCS CellMask Deep Red Stain (Life Technologies, Cat #H32721), Hoechst Stain (Life Technologies, Cat #33258), Anti-dimethyl-Arginine, sym (SYM10) antibody (Millipore, 07-412).
  • Cells were plated at 400 cells/40 ⁇ L/well in 384 well black plates ⁇ clear bottom (Perkin Elmer) and overnight incubated at 37°C, 5% CO 2 .
  • the IC 50 Studies were performed using nine point dosing series ranging from 10 ⁇ M to 1 pM for each compound. 80 nL of the respective dilution of the compounds was added using the Labcyte POD 810 (Labcyte) reaching a final DMSO concentration of 0.2% in cell culture. After an incubation period of 48h at 37°C and 5% CO 2 , cells were fixed in 10% formalin solution for 15 min at r.t. and 20 min in ice-cold MeOH, after which they were washed 3x in DPBS.
  • the cells were blocked for 1 h in blocking buffer (PBS + 1% BSA and 0.5% Triton X-100) and incubated overnight at 4°C with the SYM10 antibody diluted 1/2000 in blocking buffer.
  • the cells were washed 3x with washing buffer (PBS + 0.1% Triton X-100) and incubated with the Alexa fluor 488 goat anti-rabbit antibody diluted 1/200 in blocking buffer for 1 h at r.t.. Subsequently, they were washed 3x with washing buffer and incubated for 30 min at r.t.
  • variable names normalized
  • the normalized feature value raw The raw feature value lowMedian
  • IC 50 and pIC 50 (-logIC 50 ) values were calculated using the appropriate software.
  • pIC 50 values (Co. No. means compound number; n.d. means not determined).
  • Active ingredient (a.i.) as used throughout these examples relates to compounds of Formula (I), and pharmaceutically acceptable addition salts, and solvates thereof; in particular to any one of the exemplified compounds.
  • An aqueous suspension is prepared for oral administration so that each milliliter contains 1 to 5 mg of active ingredient, 50 mg of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol and water ad 1 ml.
  • a parenteral composition is prepared by stirring 1.5 % (weight/volume) of active ingredient in 0.9 % NaCl solution or in 10 % by volume propylene glycol in water.
  • active ingredient can be replaced with the same amount of any of the compounds according to the present invention, in particular by the same amount of any of the exemplified compounds.

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Claims (16)

  1. Verbindung der Formel (I)
    Figure imgb0562
     wobei
    R1 für Wasserstoff oder CH3 steht;
    R2 für Wasserstoff steht;
    Ra für Wasserstoff oder -C(=O)-C1-4-Alkyl steht;
    Rb für Wasserstoff oder -C(=O)-C1-4-Alkyl steht;
    Y für -O-, -CH2- oder -CF2- steht;
    R7a für Wasserstoff steht;
    R7b für Wasserstoff oder C1-4-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, steht;
    X1 für eine kovalente Bindung oder -O-steht;
    X2 für eine kovalente Bindung, -CH2-, -CF2-, -CH2CH2-, -CF2CH2- oder -CH2CF2- steht;
    mit der Maßgabe, dass X2 für eine kovalente Bindung, -CH2- oder -CF2- steht, wenn X1 für -O- steht;
    X3 für N oder CH steht oder in dem Fall, dass eine der gestrichelten Linien für eine zusätzliche Bindung steht, X3 für C steht;
    R8 und R10 jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen und C1-6-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind;
    R9 und R11 jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen, -NH2 und C1-6-Alkyl, das gegebenenfalls durch ein -NR9aR9b substituiert ist, ausgewählt sind;
    oder R8 und R9 miteinander verknüpft sind und zusammen mit dem gemeinsamen Kohlenstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein oder zwei N-Atome und gegebenenfalls ein Sauerstoffatom enthält, bilden; wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder mehreren Ringkohlenstoffatomen durch einen oder mehrere Substituenten, die jeweils unabhängig aus der Gruppe bestehend aus Halogen und C1-6-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind, substituiert ist und wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder zwei Ring-N-Atomen durch einen Substituenten aus der Gruppe bestehend aus C1-6-Alkyl, Het1a, C3-6-Cycloalkyl, -C1-4-Alkyl-C(=O) - NR5aR5b, C1-4-Alkyl, das durch ein oder mehrere Halogenatome substituiert ist, und C1-4-Alkyl, das durch einen Substituenten aus der Gruppe bestehend aus-O-C1-4-Alkyl, Cyano, C3-6-Cycloalkyl, Ar1a, -O-Ar1a, Het2a und -O-Het2c substituiert ist, substituiert ist;
    oder R10 und R11 miteinander verknüpft sind und zusammen mit dem gemeinsamen Kohlenstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein oder zwei N-Atome und gegebenenfalls ein Sauerstoffatom enthält, bilden; wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder mehreren Ringkohlenstoffatomen durch einen oder mehrere Substituenten, die jeweils unabhängig aus der Gruppe bestehend aus Halogen und C1-6-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind, substituiert ist und wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder zwei Ring-N-Atomen durch einen Substituenten aus der Gruppe bestehend aus C1-6-Alkyl, Het1b, C3-6-Cycloalkyl, -C1-4-Alkyl-C(=O) - NR6aR6b, C1-4-Alkyl, das durch ein oder mehrere Halogenatome substituiert ist, und C1-4-Alkyl, das durch einen Substituenten aus der Gruppe bestehend aus-O-C1-4-Alkyl, Cyano, C3-6-Cycloalkyl, Ar1b, -O-Ar1b, Het2b und -O-Het2d substituiert ist, substituiert ist;
    Z für -CH2-, -C(=O)- oder -CH(C1-4-Alkyl)- steht und in dem Fall, dass X3 für C steht, Z auch für =CHstehen kann;
    die gestrichelten Linien, die an X3 gebunden sind, fakultative Bindungen sind, die vorhanden sein können, wenn X3 für ein Kohlenstoffatom steht, mit der Maßgabe, dass maximal eine der gestrichelten Linien für eine fakultative Bindung steht; in dem Fall, dass eine der gestrichelten Linien, die an X3 gebunden sind, für eine zusätzliche Bindung steht, X3 für C steht und (i) R7a fehlt oder (ii) R8 fehlt oder (iii) Z für =CH- steht;
    R9a und R9b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und C1-4-Alkyl ausgewählt sind oder R9a und R9b miteinander verknüpft sind und zusammen mit dem gemeinsamen Stickstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges Heterocyclyl, das gegebenenfalls ein Sauerstoffatom enthält, bilden;
    R5a und R5b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und C1-4-Alkyl ausgewählt sind;
    Het1a und Het1b über ein beliebiges verfügbares Ringkohlenstoffatom an den Rest des Moleküls der Formel (I) gebunden sind;
    Het1a und Het1b jeweils unabhängig für ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein oder zwei Heteroatome, die jeweils unabhängig aus O, S, S(=O)p und N ausgewählt sind, enthält, stehen; Ar1a und Ar1b jeweils unabhängig für Phenyl, das gegebenenfalls durch einen oder mehrere Substituenten, die jeweils unabhängig aus der Gruppe bestehend aus Halogen, Cyano und C1-4-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind, substituiert ist, stehen;
    Het2a und Het2b jeweils unabhängig für ein 4-, 5-, 6- oder 7-gliedriges monocyclisches aromatisches oder nichtaromatisches Heterocyclyl, das mindestens ein Heteroatom, das jeweils unabhängig aus O, S, S(=O)p und N ausgewählt ist, enthält, oder ein anelliertes 8-, 9-, 10- oder 11-gliedriges bicyclisches aromatisches oder nichtaromatisches Heterocyclyl, das mindestens ein Heteroatom, das jeweils unabhängig aus O, S, S(=O)p und N ausgewählt ist, enthält, stehen; wobei das monocyclische Heterocyclyl oder das anellierte bicyclische Heterocyclyl gegebenenfalls durch einen oder mehrere Substituenten, die jeweils unabhängig aus der Gruppe bestehend aus Halogen, Cyano und C1-4-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind, substituiert ist;
    Het2c und Het2d über ein beliebiges verfügbares Ringkohlenstoffatom an den Rest des Moleküls der Formel (I) gebunden sind;
    Het2c und Het2d jeweils unabhängig für ein 4-, 5-, 6- oder 7-gliedriges monocyclisches aromatisches oder nichtaromatisches Heterocyclyl, das mindestens ein Heteroatom, das jeweils unabhängig aus O, S, S(=O)p und N ausgewählt ist, enthält, oder ein anelliertes 8-, 9-, 10- oder 11-gliedriges bicyclisches aromatisches oder nichtaromatisches Heterocyclyl, das mindestens ein Heteroatom, das jeweils unabhängig aus O, S, S(=O)p und N ausgewählt ist, enthält, stehen; wobei das monocyclische Heterocyclyl oder das anellierte bicyclische Heterocyclyl gegebenenfalls durch einen oder mehrere Substituenten, die jeweils unabhängig aus der Gruppe bestehend aus Halogen, Cyano und C1-4-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind, substituiert ist;
    R6a und R6b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und C1-4-Alkyl ausgewählt sind;
    p für 1 oder 2 steht;
    Het für ein bicyclisches aromatisches heterocyclisches Ringsystem steht, das aus der Gruppe bestehend aus (a-1), (a-2), (a-3) und (a-4) ausgewählt ist:
    Figure imgb0563
    R3a, R3b, R3c und R3d jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen, -NR12aR12b, C1-4-Alkyl und -O-C1-4-Alkyl ausgewählt sind;
    R12a und R12b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, C3-6-Cycloalkyl, C1-4-Alkyl und C1-4-Alkyl, das durch ein Phenyl substituiert ist, welches gegebenenfalls durch einen oder mehrere Substituenten aus der Gruppe bestehend aus Halogen, Cyano, -O-C1-4-Alkyl, -OH und C1-4-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, substituiert ist, ausgewählt sind;
    R4a, R4b, R4c, R4d, R4e und R4f jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen, -NR13aR13b und C1-4-Alkyl ausgewählt sind; R13a und R13b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und C1-4-Alkyl ausgewählt sind;
    Q1 für N oder CR14a steht;
    Q2 für N oder CR14b steht;
    Q3 für N oder CR14c steht;
    Q4 für N oder CR14d steht;
    mit der Maßgabe, dass maximal eines von Q3 und Q4 für N steht;
    Q8 für N oder CR14g steht;
    Q9 für N oder CR14h steht;
    Q5 für CR3d steht; Q6 für N steht und Q7 für CR4f steht oder
    Q5 für CR3d steht; Q6 für CR4e steht und Q7 für N steht oder
    Q5 für N steht; Q6 für CR4e steht und Q7 für CR4f steht oder
    Q5 für N steht; Q6 für CR4e steht und Q7 für N steht oder
    Q5 für N steht; Q6 für N steht und Q7 für CR4f steht oder
    Q5 für N steht; Q6 für N steht und Q7 für N steht; R14a, R14b, R14c, R14d, R14e, R14f, R14g und R14h jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen, C1-4-Alkyl; -NR15aR15b und C1-4-Alkyl, das durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind;
    R15a und R15b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und C1-4-Alkyl ausgewählt sind;
    mit der Maßgabe, dass R10 und R11 nicht miteinander verknüpft sein können, wenn R8 und R9 miteinander verknüpft sind;
    und wobei mindestens eines von R8, R9, R10 und R11 ein Stickstoffatom enthält;
    oder ein pharmazeutisch unbedenkliches Additionssalz oder Solvat davon.
  2. Verbindung nach Anspruch 1, wobei
    Het für ein bicyclisches aromatisches heterocyclisches Ringsystem steht, das aus der Gruppe bestehend aus (a-1), (a-2) und (a-3) ausgewählt ist.
  3. Verbindung nach Anspruch 2, wobei
    R1 für Wasserstoff steht;
    Y für -O- oder -CH2- steht;
    R7b für Wasserstoff oder C1-4-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, steht;
    X2 für eine kovalente Bindung, -CH2-, -CF2CH2- oder - CH2CF2- steht;
    mit der Maßgabe, dass X2 für eine kovalente Bindung oder -CH2- steht, wenn X1 für -O- steht;
    X3 für N steht oder in dem Fall, dass eine der gestrichelten Linien für eine zusätzliche Bindung steht, X3 für C steht;
    R8 und R10 jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen und C1-6-Alkyl, das gegebenenfalls durch ein oder mehrere Halogenatome substituiert ist, ausgewählt sind;
    R9 und R11 jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen, -NH2 und C1-6-Alkyl, das gegebenenfalls durch ein -NR9aR9b substituiert ist, ausgewählt sind;
    oder R8 und R9 miteinander verknüpft sind und zusammen mit dem gemeinsamen Kohlenstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein oder zwei N-Atome enthält, bilden; wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder zwei Ring-N-Atomen durch einen Substituenten aus der Gruppe bestehend aus C1-6-Alkyl, Het1a, C3-6-Cycloalkyl, -C1-4-Alkyl-C(=O) - NR5aR5b, C1-4-Alkyl, das durch ein oder mehrere Halogenatome substituiert ist, und C1-4-Alkyl, das durch einen Substituenten aus der Gruppe bestehend aus -O-C1-4-Alkyl, Cyano, C3-6-Cycloalkyl, Ar1a, -O-Ar1a und Het2a substituiert ist, substituiert ist; oder R10 und R11 miteinander verknüpft sind und zusammen mit dem gemeinsamen Kohlenstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein oder zwei N-Atome und gegebenenfalls ein Sauerstoffatom enthält, bilden; wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder mehreren Ringkohlenstoffatomen durch einen oder mehrere Halogensubstituenten substituiert ist und wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem oder zwei Ring-N-Atomen durch einen Substituenten aus der Gruppe bestehend aus C1-6-Alkyl und C1-4-Alkyl, das durch ein Ar1b substituiert ist, substituiert ist;
    Z für -CH2- oder -C(=O)- steht und in dem Fall, dass X3 für C steht, Z auch für =CH- stehen kann;
    die gestrichelten Linien, die an X3 gebunden sind, fakultative Bindungen sind, die vorhanden sein können, wenn X3 für ein Kohlenstoffatom steht, mit der Maßgabe, dass maximal eine der gestrichelten Linien für eine fakultative Bindung steht; in dem Fall, dass eine der gestrichelten Linien, die an X3 gebunden sind, für eine zusätzliche Bindung steht, X3 für C steht und (i) R7a fehlt oder (ii) R8 fehlt oder (iii) Z für =CH- steht;
    Het1a über ein beliebiges verfügbares Ringkohlenstoffatom an den Rest des Moleküls der Formel (I) gebunden ist;
    Het1a für ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein oder zwei Heteroatome, die jeweils unabhängig aus O ausgewählt sind, enthält, steht;
    Ar1a und Ar1b jeweils unabhängig für Phenyl, das gegebenenfalls durch einen oder mehrere Halogensubstituenten substituiert ist, stehen;
    Het2a für ein 4-, 5-, 6- oder 7-gliedriges monocyclisches aromatisches oder nichtaromatisches Heterocyclyl, das mindestens ein Heteroatom, das jeweils unabhängig aus O, S, S(=O)p und N ausgewählt ist, enthält, oder ein anelliertes 8-, 9-, 10- oder 11-gliedriges bicyclisches aromatisches oder nichtaromatisches Heterocyclyl, das mindestens ein Heteroatom, das jeweils unabhängig aus O, S, S(=O)p und N ausgewählt ist, enthält, stehen; wobei das monocyclische Heterocyclyl oder das anellierte bicyclische Heterocyclyl gegebenenfalls durch einen oder mehrere C1-4-Alkylsubstituenten substituiert ist;
    R3a, R3b und R3c jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, Halogen und -NR12aR12b ausgewählt sind;
    R12a und R12b jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff, C3-6-Cycloalkyl, C1-4-Alkyl und C1-4-Alkyl, das durch ein Phenyl substituiert ist, welches gegebenenfalls durch einen oder mehrere Halogensubstituenten substituiert ist, ausgewählt sind;
    R4a, R4b und R4c jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und C1-4-Alkyl ausgewählt sind;
    Q1 für CR14a steht;
    Q2 für N oder CR14b steht;
    Q3 für CR14c steht;
    Q4 für N steht;
    R14a, R14b, R14c, R14e und R14f jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und Halogen ausgewählt sind;
    mit der Maßgabe, dass R10 und R11 nicht miteinander verknüpft sein können, wenn R8 und R9 miteinander verknüpft sind;
    und wobei mindestens eines von R8, R9, R10 und R11 ein Stickstoffatom enthält.
  4. Verbindung nach Anspruch 2, wobei
    R1 für Wasserstoff steht;
    Y für -O- oder -CH2- steht;
    R7b für Wasserstoff steht;
    X2 für eine kovalente Bindung oder -CH2- steht;
    X3 für N steht oder in dem Fall, dass eine der gestrichelten Linien für eine zusätzliche Bindung steht, X3 für C steht;
    R8 und R10 jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und Halogen ausgewählt sind;
    R9 und R11 jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und Halogen ausgewählt sind;
    oder R8 und R9 miteinander verknüpft sind und zusammen mit dem gemeinsamen Kohlenstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein N-Atom enthält, bilden; wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem Ring-N-Atom durch C1-6-Alkyl substituiert ist;
    oder R10 und R11 miteinander verknüpft sind und zusammen mit dem gemeinsamen Kohlenstoffatom, an das sie gebunden sind, ein 4-, 5-, 6- oder 7-gliedriges gesättigtes Heterocyclyl, das ein N-Atom enthält, bilden; wobei das 4-, 5-, 6- oder 7-gliedrige gesättigte Heterocyclyl gegebenenfalls an einem Ring-N-Atom durch C1-6-Alkyl substituiert ist;
    mit der Maßgabe, dass R10 und R11 oder R8 und R9 miteinander verknüpft sind;
    Z für -CH2- steht und in dem Fall, dass X3 für C steht, Z auch für =CH- stehen kann;
    die gestrichelten Linien, die an X3 gebunden sind, fakultative Bindungen sind, die vorhanden sein können, wenn X3 für ein Kohlenstoffatom steht, mit der Maßgabe, dass maximal eine der gestrichelten Linien für eine fakultative Bindung steht; in dem Fall, dass eine der gestrichelten Linien, die an X3 gebunden sind, für eine zusätzliche Bindung steht, X3 für C steht und (i) R7a fehlt oder (ii) R8 fehlt oder (iii) Z für =CH- steht;
    Het für ein bicyclisches aromatisches heterocyclisches Ringsystem steht, das aus der Gruppe bestehend aus (a-1) und (a-2) ausgewählt ist; R3a und R3c für NH2 stehen;
    R4a und R4c für Wasserstoff stehen;
    Q1 für CR14a steht;
    Q2 für CR14b steht;
    R14a, R14b, R14e und R14f jeweils unabhängig aus der Gruppe bestehend aus Wasserstoff und Halogen ausgewählt sind.
  5. Verbindung nach einem der Ansprüche 1 bis 4, wobei Ra und Rb für -C(=O)-C1-4-Alkyl stehen.
  6. Verbindung nach einem der Ansprüche 1 bis 4, wobei Ra und Rb für Wasserstoff stehen.
  7. Verbindung nach einem der Ansprüche 1 bis 6, wobei R1 und R2 für Wasserstoff stehen.
  8. Verbindung nach einem der Ansprüche 1 bis 7, wobei X3 für C oder CH steht.
  9. Verbindung nach einem der Ansprüche 1 bis 7, wobei X3 für N steht.
  10. Verbindung nach einem der Ansprüche 1 bis 9, wobei Het für ein bicyclisches aromatisches heterocyclisches Ringsystem der Formel (a-1) steht.
  11. Verbindung nach Anspruch 10, wobei
    R3a für -NR12aR12b steht und R12a und R12b für Wasserstoff stehen.
  12. Verbindung nach einem der Ansprüche 1 bis 11, wobei R10 und R11 oder R8 und R9 miteinander verknüpft sind.
  13. Pharmazeutische Zusammensetzung, umfassend einen pharmazeutisch unbedenklichen Träger und als Wirkstoff eine therapeutisch wirksame Menge einer Verbindung nach einem der Ansprüche 1 bis 12.
  14. Verbindung gemäß einem der Ansprüche 1 bis 12 zur Verwendung als Medikament.
  15. Verbindung gemäß einem der Ansprüche 1 bis 12 zur Verwendung bei der Behandlung oder Prävention einer Erkrankung oder eines Leidens, das bzw. die aus einer Blutstörung, Stoffwechselstörungen, Autoimmunstörungen, Krebs, entzündlichen Erkrankungen, Herz-Kreislauf-Erkrankungen, neurodegenerativen Erkrankungen, Pankreatitis, multiplem Organversagen, Nierenerkrankungen, Thrombocytenaggregation, Spermienmotilität, Transplantatabstoßung und Lungenverletzungen ausgewählt ist.
  16. Verbindung zur Verwendung nach Anspruch 15, wobei es sich bei der Erkrankung bzw. dem Leiden um Krebs handelt.
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CN108884108B (zh) 2021-08-31
AU2017230658B2 (en) 2021-03-04
IL261559B (en) 2021-09-30
KR20180116307A (ko) 2018-10-24
CA3016096C (en) 2023-10-17
EP3426664A1 (de) 2019-01-16
CA3016096A1 (en) 2017-09-14
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